Direct evidence indicates that both Abs and CD8+ T cells contribute to restriction of simian immunodeficiency virus (SIV) replication. In the case of CD4+ T cells, however, it has been difficult to ascertain their contribution as they are also the target for viral infection. SIVmac251 infection of macaques is an excellent model whereby to assess these questions. As preventive vaccination with T cell vaccines ameliorates the virological outcome following viral challenge, we explored strategies to augment virus-specific immune responses in already infected macaques treated with antiretroviral therapy (ART). We demonstrated that CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Regulatory T (Treg) cells are a subset of CD25+CD4+ T cells that constitutively express high levels of cytotoxic T lymphocyte antigen-4 (CTLA-4) and suppress T-cell activation and effector functions. Treg cells are increased in tissues of individuals infected with HIV-1 and macaques infected with simian immunodeficiency virus (SIVmac251). In HIV-1 infection, Treg cells could exert contrasting effects: they may limit viral replication by decreasing immune activation, or they may increase viral replication by suppressing virusspecific immune response. Thus, the outcome of blocking Treg function in HIV/SIV should be empirically tested. We demonstrated that CD25+ T cells inhibit virus-specific T-cell responses in cultured T cells from blood and lymph nodes of SIV-infected macaques. We investigated the impact of CTLA-4 blockade using the anti-CTLA-4 human antibody MDX-010 in SIV-infected macaques treated with antiretroviral therapy (ART). CTLA-4 blockade decreased expression of the tryptophan-depleting enzyme IDO and the level of the suppressive cytokine transforming growth factor-beta (TGF-beta) in tissues. CTLA-4 blockade was associated with decreased viral RNA levels in lymph nodes and an increase in the effector function of both SIV-specific CD4+ and CD8+ T cells. Therefore, blunting Treg function in macaques infected with SIV did not have detrimental virologic effects and may provide a valuable approach to complement ART and therapeutic vaccination in the treatment of HIV-1 infection. Acute HIV/SIV infection results in severe CD4+ T cell depletion in lymphoid compartments. During the chronic phase of infection, CD4+ T cell numbers rebound in blood but remain low in the gut-associated lymphoid tissue (GALT), even when viral replication is suppressed by ART. Thus, strategies to repopulate lymphoid compartments may ameliorate the clinical outcome of HIV/SIV infection. Interleukin (IL)-7 is a key cytokine for the maintenance of homeostatic proliferation of T cells. In HIV/SIV infection, IL-7 expression is increased, likely to compensate for T cell loss, suggesting that supraphysiological administration of IL-7 could provide additional benefit. However, the ability of T cells to respond to IL-7 is dependent on the level of expression of the IL-7 receptor (IL-7R) in T cells in various body compartments. We investigated the proportion of IL-7R+ T cells in blood, spleen, gut, and genitourinary tract of healthy and SIV-infected macaques with various degrees of CD4+ T cell depletion. We found that the percentage of T cells expressing IL-7R was significantly lower in both CD4+ and CD8+ T cell subsets in SIV-infected macaques than in healthy animals and this decrease directly correlated with the CD4+ T cell number. Importantly, the proportion of CD4+ and CD8+ T cells expressing IL-7R in blood paralleled that found in tissues. IL-7R+ T cells within the SIV-specific CD8+ T cells varied and were lowest in most tissues of viremic macaques, likely reflecting continuous antigen stimulation of effector cells. We showed that IL-15 abrogates vaccine-induced decrease in virus level in SIVmac251-infected macaques. The loss of CD4+ T cells and the impairment of CD8+ T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIVmac251-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4+ or CD8+ memory T cells, clonal recruitment to the SIV-specific CD8+ T cell pool, or CD8+ T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4+ effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-beta expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals. Over the years, our preclinical data provided proof of principle for the initiation and continuation of human trials. ALVAC-HIV-based vaccine candidates are now in a phase III trial in adults in Thailand and a phase I trial in neonates in Uganda is being prepared. The combination of DNA plus NYVAC-HIV will be tested by EuroVac in healthy volunteers. Lastly, therapeutic phase I and II trials with ALVAC-HIV are ongoing at several sites and I plan to perform a phase I therapeutic trial with NYVAC-HIV in the U.S